The present disclosure relates to genetically modified non-human animals that express a fusion protein including B2M and FcRn, and methods of use thereof. In some embodiments, the animals can have a B-NDG background. In some embodiments, the endogenous B2M gene is knocked out in the animals.

Provided are a humanized transgenic non-human animal, especially a rodent, in particular a transgenic mouse containing a human interleukin 17A (IL-17A) gene, a human gene 17RA (IL-17RA) and/or a human TNF-alpha gene, and a preparation method therefor and the use thereof.

The present invention provides genetically modified non-human animals which are deficient in at least one or more types of CD3 genes selected from the group consisting of endogenous CD3ε, CD3δ, and CD3γ in its genome and functionally express at least one or more types of human CD3 genes selected from the group consisting of human CD3ε, CD3δ, and CD3γ. In the genetically modified non-human animals of the present invention, mature T cell differentiation and production can take place, and immunocompetent cells including T cells can exert their functions. The genetically modified non-human animals of the present invention enable efficient evaluation and screening in the development of therapeutic agents and therapeutic methods that use human CD3-mediated targeted drugs.

The present invention provides a method of constituting a tissue construct in vitro using a tissue without depending on scaffold materials. A method of integrating a biological tissue with a vascular system in vitro, comprising coculturing a biological tissue with vascular cells and mesenchymal cells. A biological tissue which has been integrated with a vascular system by the above-described method. A method of preparing a tissue or an organ, comprising transplanting the biological tissue described above into a non-human animal and differentiating the biological tissue into a tissue or an organ in which vascular networks have been constructed. A method of regeneration or function recovery of a tissue or an organ, comprising transplanting the biological tissue described above into a human or a non-human animal and differentiating the biological tissue into a tissue or an organ in which vascular networks have been constructed. A method of preparing a non-human chimeric animal, comprising transplanting the biological tissue described above into a non-human animal and differentiating the biological tissue into a tissue or organ in which vascular networks have been constructed. A method of evaluating a drug, comprising using at least one member selected from the group consisting of the biological tissue described above, the tissue or organ prepared by the method described above, and the non-human chimeric animal prepared by the method described above. A composition for regenerative medicine, comprising a biological tissue which has been integrated with a vascular system by the method described above.

Provided herein are transgenic non-human animals whose genomes comprise two or more human genes selected from TREM1, TREML1, TREM2, TREML2, and TREML4, to methods of screening candidate agents that bind to and/or modulate the function and/or activity of at least one of the human genes in the transgenic non-human animals, and to methods of screening candidate agents to determine their effect on one or more activities and/or functions associated with expression of at least one of the human genes in the transgenic non-human animals. Further provided herein are methods of recapitulating a human TREM immune system in a non-human animal, and methods of generating a non-human animal disease model comprising a human TREM repertoire.

Disclosed herein are non-human animals (e.g., rodents, e.g., mice or rats) genetically engineered to express a humanized T cell co-receptor (e.g., humanized CD4 and/or CD8 (e.g., CD8α and/or CD8β)), a human or humanized T cell receptor (TCR) comprising a variable domain encoded by at least one human TCR variable region gene segment and/or a human or humanized major histocompatibility complex that binds the humanized T cell co-receptor (e.g., human or humanized MHC II (e.g., MHC II α and/or MHC II β chains) and/or MHC I (e.g., MHC Iα) respectively, and optionally human or humanized β2 microglobulin). Also provided are embryos, tissues, and cells expressing the same. Methods for making a genetically engineered animal that expresses at least one humanized T cell co-receptor (e.g., humanized CD4 and/or CD8), at least one humanized MHC that associates with the humanized T cell co-receptor (e.g., humanized MHC II and/or MHC I, respectively) and/or the humanized TCR are also provided. Methods for using the genetically engineered animals that mount a substantially humanized T cell immune response for developing human therapeutics are also provided.

Provided herein are mice that are heterozygous knock outs for Ctla4 and homozygous knockouts for Pdcd1 (Ctla4.sup.+/− Pdcd1.sup.−/− mice), which may suffer from autoimmunity, including myocarditis and insulin-dependent diabetes mellitus. Also provided are methods of using such mice to screen for therapeutic agents that mitigate immune-related adverse events.

The present invention is based, in part, on the identification of methods of modulating PD-1 expression and/or activity in regulatory T cells (Tregs) to thereby regulate effector immune responses in effector T cells (Teffs).

The present invention provides a method of constituting a tissue construct in vitro using a tissue without depending on scaffold materials.

A method of integrating a biological tissue with a vascular system in vitro, comprising coculturing a biological tissue with vascular cells and mesenchymal cells. A biological tissue which has been integrated with a vascular system by the above-described method. A method of preparing a tissue or an organ, comprising transplanting the biological tissue described above into a non-human animal and differentiating the biological tissue into a tissue or an organ in which vascular networks have been constructed. A method of regeneration or function recovery of a tissue or an organ, comprising transplanting the biological tissue described above into a human or a non-human animal and differentiating the biological tissue into a tissue or an organ in which vascular networks have been constructed. A method of preparing a non-human chimeric animal, comprising transplanting the biological tissue described above into a non-human animal and differentiating the biological tissue into a tissue or organ in which vascular networks have been constructed. A method of evaluating a drug, comprising using at least one member selected from the group consisting of the biological tissue described above, the tissue or organ prepared by the method described above, and the non-human chimeric animal prepared by the method described above. A composition for regenerative medicine, comprising a biological tissue which has been integrated with a vascular system by the method described above.

The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) IL6R and/or IL6, and methods of use thereof.